Drug addiction is a major health problem in the U.S. Although there have been significant advances in our understanding the neurochemical changes in addiction, there is a need to develop new approaches and to identify novel targets for elucidating the molecular underpinnings of drug addiction. In this R21 proposal, this fundamental need will be addressed by integrating a mouse behavioral model for psychostimulant addiction with electrophysiological, molecular and cellular techniques to investigate the role of two novel proteins implicated in psychostimulant addiction, G protein-gated potassium (GIRK) channels and sorting nexin 27 (SNX27). GIRK channels have been implicated previously in drug efficacy in the mesolimbic dopamine pathway. SNX27 has been shown to associate directly with GIRK channels, leading to down-regulation of channels on the plasma membrane. Whether inhibition mediated by GABAB receptor activation of GIRK channels is reduced in dopamine neurons of the ventral tegmental area (VTA) from mice sensitized to methamphetamine remains an important unanswered question. Furthermore, it is unknown if a stimulant-induced increase in SNX27, which could be involved in the down-regulation of GIRK channels, occurs in the VTA of mice sensitized to methamphetamine. To address these, (1) GIRK channel currents in the dopamine neurons of the VTA will be measured in control and methamphetamine-sensitized mice, and (2) immunohistochemical studies will determine whether changes in protein levels occur. The potential interaction of SNX27 with GIRK channels in a model of psychostimulant addiction has the potential to enhance health-related research on drug addiction. Current drug treatments for addiction fail to address the underlying causes of addiction and current pharmacological treatments are lacking. Identifying key proteins and changes in neural circuitry in addiction could lead to the development of novel pharmacological therapies for treating addiction. The proposed work in this proposal will provide a direct molecular pharmaceutical target to treat the underlying cause, rather than the symptoms of addiction, directly benefiting human health. PUBLIC HEALTH RELEVANCE: Neuronal connections in the drug reward center of the brain change with chronic use of drugs, leading to addiction and dependence. The goal of this grant is to learn more about which proteins are changed by chronic use of methamphetamines and to also explore whether potassium channel signaling is altered. Results from these experiments may help identify novel therapeutic strategies for treating drug addiction.